1. Field of the Invention
This invention relates to a filter unit suitable for the production of suspended lipid particles represented by emulsions and liposomes, a high-pressure sizing apparatus, a method for the production of suspended lipid particles finely divided uniformly (homogeneously) within a prescribed range, and a method for the production of a membrane filter cassette.
2. Description of the Related Art
Suspensions of lipid, particles such as, for example, emulsions having water and oil emulsified by the use of amphophilic lipids and liposomes possessed of an internal water core and allowed to form a closed lipid bilayer membrane are known to those skilled in the art. The suspension of lipid particles of this type or class have been arousing much interest in the feasibilization thereof in applications for example to such pharmacological products as antitumor drugs and anti AIDS drugs, applications to products of the food industry, and applications to products of the cosmetic industry. The suspended lipid particles of this class, incidentally, are desired to have a limited average particle diameter and a predetermine or limited particle size distribution.
In response to the desire to attain uniform sizing of these lipid particles, methods such as are cited below are adopted for finely dividing and uniformly sizing the aforementioned suspended lipid particles: (a) A method of production of finely divided lipid particles which effects fine division and uniform sizing of lipid particles by making use of the mechanical shear strength, such as of a high pressure homogenizer (American Biotechnology Laboratory, volume 3, P. 36 to 41, 1985), and (b) a method of production of finely divided lipid particles which attains fine division and uniform sizing of lipid particles by forcing the lipid particles through a filtering device or a filter by exertion of a pressure in the range of 1 to 7 kgf/cm.sup.2.
The expression "method for production of suspended lipid particles", as used herein, means the act of finely dividing and uniformly sizing the lipid particles in the suspended lipid particles produced, in advance or prior to finely dividing and uniformly sizing the lipid particles as described above. The aforementioned emulsions and liposomes are cited as representing the suspended lipid particles which answer the description given above. These suspended lipid particles are prepared by using phospholipid, such as lecithins and sphingomyelins; lipids such as cholesterol, dicetyl phosphate, diglycerides, triglycerides, and tocopherols; glycolipids, such as gangliosides; nonionic surfactants, such as polyoxyethylene sorbitan fatty acid esters and polyethylene glycol fatty acid esters; and ionic surfactants such as sodium lauryl sulfate, as raw materials. Specifically, they are water-soluble drugs, lipid-soluble drugs, and oil-soluble drugs, for example.
The aforementioned methods for production of finely divided lipid particles, however, are each at a disadvantage in terms of feasibility as follows. In the case of the method described in (a) above, the great shear strength severs or degenerates part of such macromolecular drugs substances as peptides and proteins. The intense heat which results, even if partially applied, induces decomposition of drug substances which are vulnerable to heat. This method is further handicapped by the fact that accurate control of particle diameter is extremely difficult because mechanical force must be relied on for the fine division of the lipid.
In the case of the method described in (b) above, the actual practice of this method is such that the fine division of the suspended lipid particles cannot be carried out efficiently on a mass production scale due to the selection of the kind and construction of a filter such as, for example, a membrane filter, or due to the combination of the membrane filter so selected with a commercial scale, or due to the combination of selection of the kind and construction of a filter such as, for example, a membrane filter and a filter support serving the purpose of mechanically reinforcing and supporting the selected membrane filter. It may be added in this respect that the term "membrane filter" mentioned above, as used herein means what is obtained by irradiating a thin film of charged particles thereby inscribing tracks in the thin film and subjecting the tracks to a treatment for chemical corrosion thereby forming in the thin film innumerable cylindrical pores of a uniform diameter of the order of microns substantially perpendicularly to the surface of the thin film at a density, for example, of some hundreds of million pores per 1 cm.sup.2. When this membrane filter is combined with a filter support and results in, oris otherwise vested consequently with, a mechanically reinforced structure, the available area of the membrane filter is decreased and the efficiency thereof in fine division and of the uniform sizing of suspended lipid particles is degraded.
Further, when the membrane filter is produced by swelling a macromolecular material with a solvent and drying the swelled material thereby furnishing the macromolecular material with reticularly distributed micro pores therein, the resultant filter is incapable of finely dividing and uniformly sizing the aforementioned suspended lipid particles by the method that involves forcing the suspension through the filter under pressure in the aforementioned range of 1 to 7 kgf/cm.sup.2.
In any event, the method of (b) mentioned above is at an advantage with respect to the function of a filter medium in enabling the residue of filtration or filter cake deposited on the surface of thin film to be easily peeled to renew the surface and allow repeated service of the filter because filter the cake predominantly occurs on the surface of the film. It is, however, incapable of efficiently attaining necessary fine division of the suspended lipid particles on the scale of quantity production. To make the matter worse, since the filter support has a limited opening ratio, the filter support impedes the flow of suspended lipid particles which have been reduced in size by being forced through the micro pores in the membrane filter under pressure. As a result, this membrane filter prevents the necessary fine division from being efficiently attained on a mass production scale.
Incidentally, since the membrane filter is in the form of a thin film, it is put to use as supported with a supporting screen such as, for example, a flat metallic screen or a mesh screen formed of plain weave of mono-filaments, in other words in the form of a cassette or a unit.
When the membrane filter is applied closely to the supporting screen mentioned above in preparation for use, the membrane filter is degraded markedly in its capacity for filtration because the pores in the part of the membrane filter which adjoins the part of the supporting screen which is destitute or devoid of pores are closed. Alternately, in the case of a construction having a mesh screen of thin monofilaments of metal or resin interposed between the surface of a membrane filter and the surface of a supporting screen thereby separating the membrane filter and the supporting screen, the degradation of the membrane filter in the capacity for filtration can be precluded minimized or avoided. Particularly when the separation just mentioned is effected with a fine woven mesh screen, the efficiency of filtration is two to five times as high as when no separation is made.
When the membrane filter mentioned above is so constructed that the fine mesh screen of monofilaments is to be interposed between the surface of the membrane filter and that of the supporting screen each time the membrane filter is put to use as a filtering member, it entails a complicated handling which may not be considered practical. To cope with this problem, the idea of giving this membrane filter the shape of a cassette (for example) by nipping the membrane filter on the opposite main surfaces thereof between fine mesh screens identical in shape and size with the membrane filter and welding or fastening the peripheral edge part of the membrane filter, either alone or in combination with the peripheral part of a central hole forming a central concentrated flow path, with suitable resin in such a manner that the peripheral part(s) will be buried in the resin thereby ensuring unification and perfect sealing of the membrane filter, has been under test to determine feasibility thereof.
The adoption of the construction of a cassette described above allows ample elimination and preclusion of the complexity of actual use of the membrane filter. When the fine mesh screens identical in shape and size with the membrane filter are accurately adjoined to and superposed on the opposite main surfaces of the membrane filter and they are welded or fastened together with resin possessed of flexibility, a fair possibility ensues that the superposed layers will deviate from alignment or the membrane filter and the mesh screens will become loose or gather wrinkles. This construction, therefore, cannot be called satisfactory in terms of the yield of production of membrane filter cassettes and the reliability of function of the filter. For example, it is difficult to have the membrane filter and the mesh screens, which are relatively thin membranes or thin layers, accurately adjoined to each other in a thoroughly stretched state. Moreover, it is an extremely difficult task to keep the membrane filter and the mesh screens in a state producing neither wrinkle nor sag, and also to weld or fasten them in situ with flexible resin without inducing deviation or injury and attain unification and perfect sealing. The yield of production from the standpoint of outward appearance, for example, is only 40% at most. The yield of production in terms of the reliability of function (performance) is even less than 10% in consideration of the fact that membrane filter cassettes of this kind are generally put to use as superposed in a total of about 20 layers (about 100 layers at times).
Further, in the case of the method of (b) mentioned above, not only is there a problem inherent in the filter but also a device fitted with the membrane filter cassettes such as, for example, a filtering device has a problem of its own. Prerequisites for fine division and uniform sizing on, scale a mass production of the suspended lipid particles represented by emulsions and liposomes include ensuring that, (1) the sizing device is capable of being directly connected to a storage tank and capable of treating a large volume of the suspension of lipid particles at a time, (2) the sizing is preformed while excercising control of the temperature of the suspension of lipid particles under treatment to a temperature not lower than the phase transition temperature of the lipid, (3) the sizing is preformed while excercising control of the pressure of the reaction system so as to proceed in the presence of increased pressure, and (4) the sizing device exhibits a required ability to oppose corrosion when the lipid particles are intended for use in medicines (which are mostly weakly acidic or weakly basic).
The conventional filtering devices, however, do not fulfill the requirements (1) to (4) mentioned above.
As described above, membrane filter cassettes, membrane filter units, and methods and apparatus and for the production of suspended lipid particles which have been introduced to the art are not effective in ideally allowing fine division of suspended lipid particles and minimizing the range of particle diameter distribution (by uniform sizing). Thus, the desirability of developing a membrane filter cassette, a membrane filter unit, and a method and an apparatus for the production of suspended lipid particles which are capable of efficiently effecting fine division of suspended lipid particles with a minimization of the range of particle diameter distribution as by uniform sizing has been finding popular recognition.